Neurodegenerative diseases are defined as being diseases characterized by progressive dysfunction of the nervous system. They are often associated with atrophy of the structures of the central or peripheral nervous system that is affected. They include, among others, diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, lysosomal diseases, progressive supranuclear palsy, multiple sclerosis and amyotrophic lateral sclerosis. Among neurodegenerative diseases, Parkinson's disease is an affliction which affects around four million people worldwide. Although affecting individuals of any age, it is most common in older people (with 2% of the population of people older than 65 years being affected by this disease). It is characterized by degeneration of the dopaminergic neurons of the substantia nigra.
Dopamine is a neurotransmitter which plays a central part in the control of voluntary movements, in cognitive functions and in the development of behaviours associated with the emotions.
The current therapeutic strategy for the treatment of Parkinson's disease resides in attenuating the symptoms by compensating the dopamine deficiency through the administration of a metabolic precursor such as L-DOPA.
Presently, the increase in the frequency of this pathology has made it necessary to develop new therapeutic agents which play a beneficial part in neuronal differentiation and survival.
This development has led to the identification of compounds which are capable of activating the nuclear receptors involved in the pathogenesis of Parkinson's disease.
Highly expressed in the brain, the transcription factor NURR-1, a member of the orphan nuclear receptor superfamily, has been identified as having an essential role in the development and maintenance of the dopaminergic neurons of the mesencephalon (Zetterstrom, Solomin and al. 1997, Science. 1997 Apr. 11; 276(5310):248-50).
The NURR-1 nuclear receptor intervenes in the maintenance of the dopaminergic phenotype via the regulation of specific genes of the dopaminergic (DA) neurons. It also favours the survival of the DA neurons by protecting them from toxic attacks. The NURR-1 nuclear receptor therefore acts as a specific transcription factor of the dopaminergic neurons, whose activities it will be possible to regulate by modulation of dopaminergic neurotransmission in Parkinson's disease.
This receptor binds to DNA in the form of monomers, homodimers or heterodimers with RXR (Retinoid X Receptor), a nuclear receptor which is a heteropartner to many other members of the nuclear receptor family. RXR intervenes in many physiological processes, such as lipid metabolism, glucose metabolism, development and differentiation. NURR-1 thus interacts with the a and γ isoforms of RXR. The expression of RXRα is ubiquitous, whereas that of RXRγ is concentrated primarily in the brain and more particularly in the striatum, the hypothalamus and the hypophysis.
The NURR-1/RXRα and NURR-1/RXRγ complexes formed are capable of regulating transcription in reponse to a ligand of RXR. RXR therefore positively modulates the potential for activation of the transcription of NURR-1.
Identifying compounds capable of inducing the activity of the NURR-1/RXRα and NURR-1/RXRγ complexes ought therefore to allow new pathways to be made available for the treatment of Parkinson's disease.
Document WO2003/015780 discloses heterocyclic compounds which are active for the treatment of Parkinson's disease.
Furthermore, documents WO2004/072050, FR 2 903 105, FR 2 903 106 and FR 2 903 107 describe compounds which are activators of the NURR-1 receptor, while the use of heterocyclic compounds which modulate the activity of receptors of the NGFI-B family (of which NURR-1 is a member) is described in document WO2005/047268.
Lastly, document WO2005/056522 discloses indole derivatives which are activators of the PPAR nuclear receptors and find application as active principles of medicaments for the treatment of certain diseases of the cardiovascular system.
In this context it has been found—and it is this which constitutes the basis of the present invention—that certain compounds derived from indole and embraced by the general formula given in document WO2005/056522 are selective NURR-1/RXRα and NURR-1/RXRγ agonists which are capable of inhibiting the degeneration of neurons that is observed in Parkinson's disease.
Hence it has been shown that, surprisingly, the compounds of the invention, further to their PPAR activator power, exhibit a very high potential for activation of the NURR-1/RXRα and NURR-1/RXRγ heterodimers. These compounds, therefore, by virtue of their unique properties, are of particular interest with respect to their use in the treatment or prevention of diseases involving the NURR-1 receptor, especially of neurodegenerative diseases and more particularly of Parkinson's disease.
Accordingly the present invention first provides, as new products, compounds derived from indole, selected from
i) compounds of formula (I)
                in which        R1 represents a halogen or a trifluoromethyl group,        R2 represents a hydrogen atom or a C1-C4 alkyl group,        R3 represents an isopropyl (1-methylethyl) group or a tert-butyl (1,1-dimethylethyl) group and        n=3 or 4        and        
ii) pharmaceutically acceptable salts of said compounds of formula (I).
It has been observed—and this is the original nature of the compounds of the invention—that the simultaneous presence:                of an isopropyl substituent or of a tert-butyl substituent in meta position on the benzenesulphonyl group; and        of a halogen or of a trifluoromethyl group in position 5 of the indole endows the compounds of the invention with a remarkable and entirely unexpected activity with regard to NURR-1 receptors.        
The compounds of the invention therefore have a chemical structure which, although covered generally by the general formula described in document WO 2005/056522, is the result of a selection which a person skilled in the art would not have been able to carry out in searching for compounds intended for the treatment of Parkinson's disease.
The invention secondly provides the aforementioned compounds for their use as pharmacologically active substances, and also the pharmaceutical compositions comprising them.
The invention thirdly provides for the use of at least one compound of formula (I) or one of its pharmaceutically acceptable salts as an active principle for preparing a medicament intended for the treatment of diseases involving the NURR-1 receptor, especially neurodegenerative diseases, such as, more particularly, Parkinson's disease.